Meridianins Inhibit GSK3β In Vivo and Improve Behavioral Alterations Induced by Chronic Stress

• Published in: Marine Drugs
• Main Authors: Anna Sancho-Balsells, Esther García-García, Francesca Flotta, Wanqi Chen, Jordi Alberch, Manuel J. Rodríguez, Conxita Avila, Albert Giralt
• Format: Article in Journal/Newspaper
• Language: English
• Published: MDPI AG 2022
• Subjects: GSK3β; PKA; PKC; Akt; GluR1; memory; Biology (General); QH301-705.5; Antarctic; Antarc*
• Online Access: https://doi.org/10.3390/md20100648; https://doaj.org/article/ce9bf713c5f24197a5b73dc435de4295

Major depression disorder (MDD) is a severe mental alteration with a multifactorial origin, and chronic stress is one of the most relevant environmental risk factors associated with MDD. Although there exist some therapeutical options, 30% of patients are still resistant to any type of treatment. GSK3β inhibitors are considered very promising therapeutic tools to counteract stress-related affectations. However, they are often associated with excessive off-target effects and undesired secondary alterations. Meridianins are alkaloids with an indole framework linked to an aminopyrimidine ring from Antarctic marine ascidians. Meridianins could overcome several of the aforementioned limitations since we previously demonstrated that they can inhibit GSK3β activity without the associated neurotoxic or off-target effects in rodents. Here, we show that meridianins delivered into the lateral ventricle inhibited GSK3β in several brain regions involved with stress-related symptoms. We also observed changes in major signaling pathways in the prefrontal cortex (Akt and PKA) and hippocampus (PKC and GluR1). Moreover, meridianins increased synaptic activity, specifically in the CA1 but not in the CA3 or other hippocampal subfields. Finally, we chronically treated the mice subjected to an unpredictable mild chronic stress (CUMS) paradigm with meridianins. Our results showed improvements produced by meridianins in behavioral alterations provoked by CUMS. In conclusion, meridianins could be of therapeutic interest to patients with stress-related disorders such as MDD.